Abstract Despite more than a decade of widespread antiretroviral therapy (ART) implementation, Kaposi?s sarcoma (KS) remains the most common malignancy in people living with HIV-1/AIDS, in whom it causes significant morbidity and mortality [1]. Beyond a requirement for KSHV infection, the mechanisms underlying KS development are poorly understood. KS prevalence is high in people living with HIV-1 where it associates with CD4+ T-cell depletion. Thus, CD4+ T-cell functional dysregulation has been suggested to lead to KS development. Indeed, following successful ART, there is reconstitution of CD4+ T-cells [17] which often leads to KS resolution. In contrast, KS in patients with high CD4+ T-cells and low HIV-1 PVL [4?7] have been described, suggesting immune defects beyond CD4 T-cell reconstitution. In HIV-1 PVL suppressed patients, it is possible that there exist quantitative or qualitative differences in CD4+ T-cells between patients that develop KS and those who remain asymptomatic. These differences might limit the ability of CD4+ T-cells to provide help to B-cells and cytotoxic CD8+ T-cell. Alternatively, CD4+ T-cells might be fully functional in HIV-1 PVL suppressed patients but the defect is in the cytotoxic CD8+ T-cell compartment in those with KS. Chronic antigenic stimulation could induce CD8+ T-cells to states of exhaustion or anergy making them non-responsive to KSHV infected cells and KS tumors. Importantly, there are no biomarkers of KS control or its absence that can be used to identify individuals that are high risk for KS despite HIV-1 control. Our group and others have shown dysregulation of metabolic pathways in KS tumors [11?14]. Since altered metabolites often correlate with disease, identification of plasma and or urine metabolites that differentiate HIV-suppressed patients with and without KS could prove to be important KS biomarkers. Therefore, the objective of this proposal is to recruit Tanzanian HIV-1 PVL suppressed patients presenting with KS at ORCI, and age and sex-matched co- infected but asymptomatic controls from nearby CTCs in order to define immune responses and metabolomic profiles that differentiate the two groups. The hypothesis is that, distinct metabolomic and immune responses differentiate reconstituted HIV-1 suppressed patients experiencing KS from otherwise matched asymptomatic controls. Transcriptional profiling of relevant immune cell subsets and metabolomics/proteomic analysis of plasma and urine will provide mechanistic insight into the bases for the differential metabolomics/proteomics and immune responses. Therefore, the proposed study has potential to identify biomarkers for KS diagnostics, treatment management, or to identify potential immunotherapeutic or vaccine development strategies.